Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells

Microtubules (MTs) control cell shape and intracellular cargo transport. The role of MT turnover in the migration of slow-moving cells through endothelial barriers remains unclear. To irreversibly interfere with MT disassembly, we have used the MT-stabilizing agent zampanolide (ZMP) in Β16F10 melanoma as amodel of slow-moving cells. ZMP-treated B16 cells failed to follow chemotactic gradients across rigid confinements and could not generate stable sub-endothelial pseudopodia under endothelial monolayers. In vivo, ZMP-treated Β16 cells failed to extravasate though lung capillaries. In contrast to melanoma cells, the chemotaxis and transendothelial migration of ZMP-treated Tcells were largely conserved. This is afirst demonstration that MT disassembly is akey checkpoint in the directional migration of cancer cells but not of lymphocytes.

微管（Microtubules，MTs）可调控细胞形态与胞内货物运输。目前MT周转在慢速迁移细胞穿越内皮屏障过程中的作用仍不明确。为不可逆地干预MT解聚过程，我们以慢速迁移细胞模型B16F10黑色素瘤细胞为研究对象，使用MT稳定剂扎潘诺利德（zampanolide，ZMP）进行处理。经ZMP处理的B16细胞无法响应趋化梯度以穿越刚性受限环境，也无法在内皮细胞单层下方形成稳定的内皮下伪足。在活体实验中，经ZMP处理的B16细胞无法穿越肺毛细血管完成外渗。与黑色素瘤细胞不同的是，经ZMP处理的T细胞的趋化活性与跨内皮迁移能力基本得以保留。本研究首次证实，MT解聚是癌细胞定向迁移的关键检查点，但并非淋巴细胞定向迁移的关键调控节点。